«New drugs» Postgraduate Course Heart Failure Session

Transcription

1 «New drugs» Postgraduate Course Heart Failure Session Dr A. Testuz Service de cardiologie Hôpitaux Universitaires de Genève Joint annual meeting SSC/SSCS-SSP Lausanne

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3 HFrEF Positive drug, device and other trials Slide courtesy of John McMurray

4 GUIDELINES what s new? Future - HFrEF Future HFpEF /HFmrEF Future - Acute HF

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6 Sacubitril-Valsartan df PARADIGM-HF ANP BNP CNP Urodilatin McMurray J et al, EJHF 2015

7 Sacubitril-Valsartan df PARADIGM-HF 8442 patients NYHA II-III-IV EF 40% Enalapril 10 mg x 2 and OMT LCZ696 (200x2) vs enalapril (10x2) 1 : composite of death from CV cause and hospital admission for HF Stopped after 27 months because of overwhelming benefit of LCZ 696 for primary (20% reduction) and secondary endpoints (16-29% reduction). McMurray J et al, NEJM 2014

8 Treatment algorithm for patients with HFrEF ESC Guidelines 2016 ESC Guidelines for diagnosis and treatment of acute and chronic heart failure 2016

9 Neprylisin degradation of amyloid Aβ responsible of Alzheimer s disease Metabolite of LCZ696 does not seem to cross the blood-brain barrier LONG TERM SAFETY CONCERN Vodovar N et al, EHJ 2015 Langenickel TH et al, BrJ Clin Pharmacol 2016

10 Sacubitril-Valsartan CH FDA July 2015 Swissmedic for HFrEF September 2015 OFSP (reimbursment) November 2015 EU November 2015 DOSE start 100mg (or 50mg) 2x/d double at 2-4 weeks target 200mg 2x/d CI SE ACEI (36h), aliskiren (diab et IR) Clcreat <10ml/min/ PRICE 8.16 Frs/day Frs/month hypotension, renal impairment, hyperkalemia, angioedema FOLLOW-UP use NT-proBNP

11 Levosimendan advanced CHF LEVO-REP (2014, 120 patients) LION-HEART (HF congress 2015, 69 patients) 1 no change in 5-min walk test 2 reduced combined HF hosp and death endpoint (but not mortality alone) LAICA study (HF congress 2016, 97 patients) 1 hospital admission for AHF no difference 2 mortality reduction in levosimendan group STILL NOT MENTIONED IN THE GUIDELINES Safety ok Contrasting results regarding HF hospital admission and mortality Large RCT with mortality endpoint needed

12 GUIDELINES what s new? Future - HFrEF Future HFpEF/HFmrEF Future - Acute HF

13 VERICIGUAT - HFrEF Soluble guanylyl cyclase (sgc) stimulator increase cgmp Key role in HFrEF and HFp/mrEF Slide courtesy of John McMurray

14 SOCRATES-REDUCED phase II NT-proBNP level change from baseline CV death or HF hospital admission Placebo group Vericiguat mg group Gheorghiade M et al, JAMA 2015

15 Empagliflozine HFrEF SGLT2 inhibitors inhibits proximal tubular glucose reabsorption, cause diuresis and natriuresis, lower BP and reduce weight EMPA-REG-OUTCOME diabetes study 7,020 patients with T2DM and CV disease/risk factors 38% reduction in CV death 35% reduction in hospital admission for HF Zinman et al. NEJM 2015 Fitchett et al, EHJ 2016

16 GUIDELINES what s new? Future - HFrEF Future HFpEF/HFmrEF Future - Acute HF

17 RCT HFp/mrEF 107/426 (25.1)% 100/424 (23.6)% 366/1509 (24)% 333/1514 (22)% HR (CI) 0.92: ( ) P=0.55 HR (CI) 0 89 ( ) P= /2061 (37)% 742/2067 (36)% HR (CI) 0.95: ( ) P=0.35 HR (CI) 0.89: ( ) P=0.14

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19 GUIDELINES what s new? Future - HFrEF Future HFpEF/HFmrEF Future - Acute HF

20 SERELAXIN - AHF RELAXIN Multiple actions through Endothelin and NO VASODILATATION lower BP, inscreased CO INCREASES RENAL PERFUSION diuresis DECREASES INFLAMMATION DECREASES OXYDATIVE STRESS DECREASES FIBROSIS

21 SERELAXIN AHF 1 RELAX-AHF (2013) phase III, 1161 patients with AHF 30ug/kg/d or placebo 1 dyspnea (day 5) 2 CV death and readmission (day 60) -37% improvement of dyspnea, no difference in day mortality, no hypotension, less renal impairment -37% Teerlink JT et al, Lancet 2013

22 RELAX AHF 2 EXPECTED COMPLETION 2017 NCT ( Courtesy of McMurray, Heart Failure Congress 2016

23 SERELAXIN - AHF WHY LONG TERM EFFECT? 1 LESS ORGAN DAMMAGE 2 LESS WHF 3 BETTER DECONGESTION Filippatos G et al, EHJ 2014

24 df ULARITIDE - AHF Natiruretic peptide (kidney) inhibits Na reabsorption Natruresis Vasodilatation Bronchodilatation Neurohormonal (- RAA Endothelin) TRUE-AHF - RCT PHASE III, 2157 patients AHF, 15ng/kg/d 48h vs placebo 1 A. Composite score of clinical outcome and symptoms during perfusion B. CV mortality during entire trial (180 days) RESULTS IN ROME IN AUGUST 2016 SIRIUS-I and II Mitrovic V et al, Am HJ 2005, EHJ 2006 Anker SD et al, EHJ 2015 Heart Failure Congress Florence 2016

25 Omecamtiv mecarbil AHF/HFrEF Intravenous - AHF Teerlink JT et al, JACC 2016 Oral- HFrEF

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27 FUTURE PHASE III NEAR FUTURE SACUBITRIL-VALSARTAN (HFp/mrEF) SERELAXIN (AHF (HFrEF?) ULARITIDE (AHF) TO BE FOLLOWED VERICIGUAT (HFrEF HFp/mrEF?) EMPAGLIFLOZINE (HFrEF HFpEF) OMECAMTIV MECARBIL (HFrEF AHF) FINERENONE (HFpEF) NYTROXYL DONORS (AHF HFpEF) ISTAROXIME (AHF)

28 Take home dfmessages Most innovations in the last decades are in the field of HFrEF (drugs, devices) Sacubitril-valsartan is the only new drug incorporated into the guidelines ESC guidelines since 2012 (HFrEF) What about levosimendan for repetitive doses in advanced HFrEF? In HFp/mrEF no new drug, but waiting for PARAGON-HF (sacubitrilvalsartan) In actue HF no new drug, but waiting for RELAX-AHF2 (serelaxin) and TRUE-AHF (ularitide) Many drugs under phase II-III planned (vericiguat, empagliflozine, omecamtiv mecarbil, istaroxime, nitroxyl donors, finerenone, and more)

29 Thank you for your attention

30 Sacubitril-Valsartan TITRATION 498 patients No difference in tolerability, better reach of target dose with «conservative» regiment for low-dose initial ACEI Senni M et al, EJHF 2016

31 Ivabradine - SHIFT SHIFT (2010) 6658 patients NYHA II-III, EF 35%, on OMT Ivabradine ad 7.5mg x2 vs placebo + OMT 1 composite HF death and hospital admission Swedberg K et al, Lancet 2010

32 Levosimendan AHF Calcium sensitsizer Inotropic Lusitropic Vasodilation No increase of O2 consumption LIDO trial (2002) phase II 103 patients RCT with levosimendan vs dobutamine 1 Hemodynamic effect (30% increase in CO, 25% decrease in PCWP) at 24h SURVIVE study (2007) phase III 1327 patients RCT with levosimendan (with loading dose) vs dobutamine 1 All cause mortality at 180 days Survival advantage in subgroup of CHF patients recieving betablockers Class IIb, level C Preferred molecule for CHF patients recieving BB Mebazza et al, EJHF 2009 Mebazza et al, JAMA 2007

33 ATMOSPHERE-Design Primary outcome: CV death or heart failure hospitalization (event driven: target 2318 patients [2369 accrued]) Enalapril 5-10mg bid Enalapril + Aliskiren150mg qd Randomization *89% 10mg bid Target dose (titrated from 150mg qd) Enalapril 5-10mg bid* (n=2336) Aliskiren 300mg qd (n=2340) Enalapril 5-10mg bid* + Aliskiren 300mg qd (n=2340) Open-label run-in 4-12 weeks Double-blind Median follow-up = 36.6 months Prior ACEi use discontinued McMurray et al. N Engl J Med published on line April

34 ATMOSPHERE-Design McMurray et al. N Engl J Med published on line April

35 RIVAROXABAN df - HFrEF

36 COMMANDER HF: Rivaroxaban following hospitalization for HF in patients with CAD Hypothesis: Rivaroxaban will reduce morbidity and mortality in pts with HF due to CHD. Population: 5000 patients; symptomatic HF; CHD; EF 40%; BNP 200 pg/ml or NT-proBNP 800 pg/ml; recent exacerbation of HF. Intervention: Rivaroxaban (2.5mg bid) vs placebo. Primary endpoint: Death, MI or stroke. Status: Started Slide courtesy of McMurray, Heart Failure Congress Florence 2016 Faiez Z et al, EJHF 2015

37 TRV (120)027: a biased angiotensin II type 1 receptor (AT1R) ligand Boerrigter G et al. Circ Heart Fail 2011;4:

38 BLAST-HF Biased Ligand of the Angiotensin receptor Study in acute Heart Failure Hypothesis: To test the efficacy and safety of TRV027, a novel biased ligand of the angiotensin II type 1 receptor. Population: 500 patients hospitalized with AHF (systolic blood pressure 120 mm Hg and 200 mm Hg within 24 h of presentation. Intervention: 3 doses of iv TRV027 (1, 5, or 25 mg/h) or placebo (1:1:1:1) for <48 h and 96 h. Primary endpoint: composite of 5 clinical endpoints (dyspnea, worsening heart failure, length of hospital stay, 30-day rehospitalization, and 30-day mortality) combined using an average z-score.

39 Sacubitril-valsartan HFpEF PARAMOUNT (Phase II) 301 patients LVEF 45% Sacubitril-valsartan vs valsartan alone 1 change in NT-proBNP level at 12 weeks 2 reduction in LA size at 36 weeks

40 HFpEF df what else? Vericiguat (sgmp stimulator) SOCRATES-PRESERVED (Phase II) 477 patients 5 arms (2 low doses, 2 uptitration, 1 placebo) Completed september 2015 No results Empagliflozine (SGLT-2 inhibitor) EMPA-REG (phase III, diabetics) Application in HFpEF Finerenone (non-steroidal mineralocorticoid receptor antagonist) ARTS-HF (phase II) 1002 patients - Finerenone (different dose groups (5) vs eplerenone) Equal reduction in pro-bnp - less hypekaliemia Trend to better event-free survival (small groups)

41 SERELAXIN - AHF Pre-RELAX-AHF (2009) decrease dyspnea (immediate and 14 days) phase II RCT, 234 patients with AHF suggestion of beneficial effect on congestion, 4 doses (48h) or placebo worsening HF, length of stay, death and readmission at 60 days, 180-day CV mortality ULARITIDE SIRIUS-I (2005) and SIRIUS-II (2006) reduces PCWP, mortality 24 and 221 patients in AHF, 3 doses and placebo improves CI and symptoms no impairment of renal function

42 INOTROPES Omecamtiv mecarbil (cardiac myosin activator ATOMIC-AHF study (IV)) Initropic effect without increase in O2 consumption no proarrythmia 1 no change in dyspnea, but trend towards reduced WHF 2 safe Istaroxime (Na/K-ATPase inhibitor HORIZON-HF) inotropic and lusitropic effect no proarrythmia 1 decreases effectively PCWP, no phase III trial Nitroxyl donor (HNO) Inotropic, lusitropic and vasodilator (unlike NO, only vasodilator) Also potenital use in HfpEF Mitrovic V et al, Am HJ 2005, Mitrovic V et al, EHJ 2006, Anker SD et al, EHJ 2015, Heart Failure Congress Florence 2016